Downloaded from ard.bmj.com on August 31, 2014 - Published by group.bmj.com
Yes No No Yes Yes No Yes NA NA NA CS, AZA
CS CS
*Various combinations of these medications were adopted during the course of the disease †Details concerning these patients’ course have been previously reported in reference # 10. ‡These patients have not yet completed 12 months of anakinra treatment. ASA, aspirin; AZA, azathioprine; CRP, C reactive protein; CS, corticosteroids; D/C, discontinuation; F, female; M, male; NA, not applicable; NSAIDs, non-steroidal anti-inflammatory drugs; Rx, treatment. Patients numbers 4 and 8, had discontinued previous CS therapy due to side effects. In the bottom line of the table, data are expressed as mean±1 SD with the median values in parenthesis. The CS dose has been adjusted to daily prednisolone dose.
49 53 35 17 26 15 18 8 12 7 24±16 (17.5) 25 No recurrences 32 8 15 No recurrences 12 NA NA NA 18±9 (15) 6 1.5 6 12 12 12 12 8 12 7 8.8±3.7 (10) 20 10 20 NA 120 120 30 NA 45 60 53±44 (37.5) 95/7 165/9 148/6 21/3 88/5 24/4 75/6 32/6 71/10 18/3 74±52 (73)/5.9 ±2.3 (6) ASA, NSAIDs, Colchicine, NSAIDs, Colchicine, CS ASA, NSAIDs, Colchicine, ASA, NSAIDs, Colchicine, NSAIDs, Colchicine, CS ASA, NSAIDs, Colchicine, NSAIDs, Colchicine, CS NSAIDs, Colchicine, CS NSAIDs, Colchicine, CS NSAIDs, Colchicine, CS 8 6 8 7 5 15 5 9 4 14 8±3.7 (7.5) 72 18 12 48 37 61 48 50 12 15 37±22 (42) M F F M M M F F M F 26 36 19 34 22 59 53 74 42 51 42±18 (39)
Age (years) #
1† 2† 3† 4 5 6 7 8‡ 9‡ 10‡
Number of recurrences Prior medications*
CS, AZA
Baseline medications/CS (dose, mg/d)
NSAIDs, Colchicine, CS (10 mg/d) NSAIDs, Colchicine, CS (20 mg/d) NSAIDs, Colchicine, CS (15 mg/d) NSAIDs, Colchicine Colchicine, CS (30 mg/d) Colchicine, CS (15 mg/d) Colchicine, CS (7.5 mg/d) NSAIDs, Colchicine Colchicine, CS (7.5 mg/d) CS (7.5 mg/d) 14.1±7.9 (12.5)
Anakinra re-Rx Total follow-up (months) Time to first recurrence after anakinra D/C (days) Initial treatment duration (months) Time to corticosteroid discontinuation (days) Baseline CRP (mg/dL)/time to normalisation (days) Disease duration Sex (months)
Details on patient demographics, treatment, and patient course during anakinra therapy Table 1
Recurrent idiopathic pericarditis is a common, problematic complication of acute pericarditis, occurring in approximately 30% of cases.1 Despite appropriate management with non-steroidal anti-inflammatory drugs (NSAIDs), colchicine and corticosteroids (CS), a number of patients are either resistant to treatment requiring long-term therapy with high doses of CS or intolerant to therapy.2–4 This disease is currently viewed as an autoinflammatory disease based on its clinical and laboratory features (recurrent episodes of sterile serosal inflammation in the absence of specific autoreactive antibodies or T cells),5–7 and the preliminary results showing favourable response to intereleukin-1 (IL-1) inhibition.8–10 Anakinra, a known IL-1 receptor antagonist, has been successfully used in small series of paediatric patients8 9 while we have recently first reported its efficacy and safety in three adult patients.10 In this report, we extend our follow-up on these three patients, and present data on seven more adult patients treated with anakinra. Ten patients with idiopathic, treatment-resistant recurrent pericarditis treated with anakinra were included in the study. The diagnosis of recurrent pericarditis was established by the following three criteria: (1) a documented initial episode of acute pericarditis, (2) reappearance of chest pain attributable to acute pericarditis and (3) at least one of the following findings: pericardial friction rub, fever, typical electrocardiographic changes, pericardial effusion (new appearing or worsening), and C reactive protein (CRP) elevation.1–3 In all patients, a specific cause of pericarditis was excluded after a thorough evaluation including detailed clinical history and examination, laboratory evaluation and imaging studies. All patients signed an informed consent form prior to enrolment, and the study was approved by the institutional review board. All patients were resistant and/ or intolerant to previous treatment with aspirin (ASA) and/or NSAIDs, colchicine and CS, while two (20%) had failed also azathioprine therapy (table 1). The mean number of previous recurrences was 8, the mean baseline dose of prednisolone was 14.1 mg/day (n=8, 2 patients had discontinued CS due to intolerance or side effects) and the mean baseline CRP level was 74 mg/dL. The treatment protocol of the initial three patients has been previously reported.10 The next seven patients (table 1, numbers 4–10), were given daily subcutaneous anakinra (100 mg) for 6 months followed by alternate day dosing for another 6 months. This modified protocol with slower tapering of anakinra was based on our initial10 and others’8 previous experience. CS and colchicine were gradually discontinued in all patients after initial anakinra administration. In patients who had a first recurrence after anakinra discontinuation, colchicine was reintroduced during the last month of anakinra therapy. Anakinra was highly effective in all cases leading to rapid symptom relief (within 48 h), CRP normalisation (mean time 5.9 days) and tapering/discontinuation of CS (median time to discontinuation 37.5 days) Five out of 7 patients (70%), relapsed shortly (mean time to relapse 18 days) after initial anakinra discontinuation. In 4/5 patients anakinra was restarted with immediate control of symptoms, while one patient was managed successfully with colchicine and NSAIDs alone.10 Anakinra administration was generally safe, except for minor
Total number of recurrences after anakinra D/C
Anakinra for the management of resistant idiopathic recurrent pericarditis. Initial experience in 10 adult cases
3 0 1 1 1 0 1 NA NA NA
ARD Online First, published on August 27, 2014 as 10.1136/annrheumdis-2014-205990 Letter
Ann2014. Rheum Produced Dis Month 2014 by Vol 0BMJ No 0 Publishing Group Ltd (& EULAR) under licence. 1 Copyright Article author (or their employer)
Downloaded from ard.bmj.com on August 31, 2014 - Published by group.bmj.com
Letter local reactions at the injection site (6/10, 60%) and transient transaminasemia requiring drug discontinuation in one patient (table 1, number 2). In conclusion, this study confirms our previous findings that anakinra is a rapidly acting, highly efficacious, safe and steroidsparing agent for the treatment of resistant recurrent idiopathic pericarditis in adults. Nevertheless, we observed a high recurrence rate (70%) which is even higher compared with the paediatric experience (43%)8 after anakinra discontinuation. Although these recurrences were easily managed with anakinra readministration, randomised controlled trials are required to confirm its efficacy and identify the most appropriate administration protocol.
Funding Special Account for Research Grants (SARG), National and Kapodistrian University of Athens, Athens, Greece.
George Lazaros,1 Panagiotis Vasileiou,1 Christos Koutsianas,2 Katerina Antonatou,2 Christodoulos Stefanadis,1 Dimitrios Pectasides,2 Dimitrios Vassilopoulos2
REFERENCES
1
1st Department of Cardiology, University of Athens Medical School, Hippokration General Hospital, Athens, Greece 2 2nd Department of Medicine and Laboratory, Clinical Immunology and Rheumatology Unit, University of Athens Medical School, Hippokration General Hospital, Athens, Greece Correspondence to Dr Dimitrios Vassilopoulos, Clinical Immunology and Rheumatology Unit, 2nd Department of Medicine and Laboratory, Hippokration General Hospital, University of Athens School of Medicine, 114 Vass. Sophias Ave., Athens 115 27, Greece; [email protected] Acknowledgements This work was supported, in part, by research grants from the Special Account for Research Grants (SARG), National and Kapodistrian University of Athens, Athens, Greece. Contributors GL: participated in study design and supervision; data acquisition, analysis and interpretation; and drafting, revision and final approval of the report; PV: participated in data acquisition, analysis and interpretation; drafting, revision and final approval of the manuscript; CK and KA: participated in data acquisition; drafting, revision and final approval of the manuscript; CS and DP: participated in study supervision; data interpretation; and drafting, revision and final approval of the report; DV: participated in study conception, design and supervision; data acquisition, analysis and interpretation; and drafting, revision and final approval of the report.
2
Competing interests None. Ethics approval Institutional Review Board, Hippokration General Hospital. Provenance and peer review Not commissioned; externally peer reviewed. To cite Lazaros G, Vasileiou P, Koutsianas C, et al. Ann Rheum Dis Published Online First: [ please include Day Month Year] doi:10.1136/annrheumdis-2014205990 Received 26 May 2014 Revised 6 August 2014 Accepted 10 August 2014 Ann Rheum Dis 2014;0:1–2. doi:10.1136/annrheumdis-2014-205990
1 2 3
4 5 6 7 8
9
10
Imazio M. Treatment of recurrent pericarditis. Expert Rev Cardiovasc Ther 2012;10:1165–72. Lazaros G, Vlachopoulos C, Stefanadis C. Idiopathic recurrent pericarditis: searching for Ariadne’s thread. Hellenic J Cardiol 2009;50:345–51. Imazio M, Belli R, Brucato A, et al. Efficacy and safety of colchicine for treatment of multiple recurrences of pericarditis (CORP-2): a multicentre, double-blind, placebo-controlled, randomised trial. Lancet 2014;383:2232–7. Brucato A, Brambilla G, Moreo A, et al. Long-term outcomes in difficult-to-treat patients with recurrent pericarditis. Am J Cardiol 2006;98:267–71. Maestroni S, Di Corato PR, Cumetti D, et al. Recurrent pericarditis: autoimmune or autoinflammatory? Autoimmun Rev 2012;12:60–5. Dinarello CA, van der Meer JW. Treating inflammation by blocking interleukin-1 in humans. Semin Immunol 2013;25:469–84. Vasileiou P, Tsioufis C, Lazaros G, et al. Interleukin-8 as a predictor of acute idiopathic pericarditis recurrences. A pilot study. Int J Cardiol 2014;172:e463–4. Finetti M, Insalaco A, Cantarini L, et al. Long-term efficacy of interleukin-1 receptor antagonist (anakinra) in corticosteroid-dependent and colchicine-resistant recurrent pericarditis. J Pediatr 2014;164:1425–31.e1. Picco P, Brisca G, Traverso F, et al. Successful treatment of idiopathic recurrent pericarditis in children with interleukin-1beta receptor antagonist (anakinra): an unrecognized autoinflammatory disease? Arthritis Rheum 2009;60:264–8. Vassilopoulos D, Lazaros G, Tsioufis C, et al. Successful treatment of adult patients with idiopathic recurrent pericarditis with an interleukin-1 receptor antagonist (anakinra). Int J Cardiol 2012;160:66–8.
Ann Rheum Dis Month 2014 Vol 0 No 0
Downloaded from ard.bmj.com on August 31, 2014 - Published by group.bmj.com
Anakinra for the management of resistant idiopathic recurrent pericarditis. Initial experience in 10 adult cases George Lazaros, Panagiotis Vasileiou, Christos Koutsianas, et al. Ann Rheum Dis published online August 27, 2014
doi: 10.1136/annrheumdis-2014-205990
Updated information and services can be found at: http://ard.bmj.com/content/early/2014/08/27/annrheumdis-2014-205990.full.html
These include:
References
This article cites 10 articles http://ard.bmj.com/content/early/2014/08/27/annrheumdis-2014-205990.full.html#ref-list-1
P
Yes No No Yes Yes No Yes NA NA NA CS, AZA
CS CS
*Various combinations of these medications were adopted during the course of the disease †Details concerning these patients’ course have been previously reported in reference # 10. ‡These patients have not yet completed 12 months of anakinra treatment. ASA, aspirin; AZA, azathioprine; CRP, C reactive protein; CS, corticosteroids; D/C, discontinuation; F, female; M, male; NA, not applicable; NSAIDs, non-steroidal anti-inflammatory drugs; Rx, treatment. Patients numbers 4 and 8, had discontinued previous CS therapy due to side effects. In the bottom line of the table, data are expressed as mean±1 SD with the median values in parenthesis. The CS dose has been adjusted to daily prednisolone dose.
49 53 35 17 26 15 18 8 12 7 24±16 (17.5) 25 No recurrences 32 8 15 No recurrences 12 NA NA NA 18±9 (15) 6 1.5 6 12 12 12 12 8 12 7 8.8±3.7 (10) 20 10 20 NA 120 120 30 NA 45 60 53±44 (37.5) 95/7 165/9 148/6 21/3 88/5 24/4 75/6 32/6 71/10 18/3 74±52 (73)/5.9 ±2.3 (6) ASA, NSAIDs, Colchicine, NSAIDs, Colchicine, CS ASA, NSAIDs, Colchicine, ASA, NSAIDs, Colchicine, NSAIDs, Colchicine, CS ASA, NSAIDs, Colchicine, NSAIDs, Colchicine, CS NSAIDs, Colchicine, CS NSAIDs, Colchicine, CS NSAIDs, Colchicine, CS 8 6 8 7 5 15 5 9 4 14 8±3.7 (7.5) 72 18 12 48 37 61 48 50 12 15 37±22 (42) M F F M M M F F M F 26 36 19 34 22 59 53 74 42 51 42±18 (39)
Age (years) #
1† 2† 3† 4 5 6 7 8‡ 9‡ 10‡
Number of recurrences Prior medications*
CS, AZA
Baseline medications/CS (dose, mg/d)
NSAIDs, Colchicine, CS (10 mg/d) NSAIDs, Colchicine, CS (20 mg/d) NSAIDs, Colchicine, CS (15 mg/d) NSAIDs, Colchicine Colchicine, CS (30 mg/d) Colchicine, CS (15 mg/d) Colchicine, CS (7.5 mg/d) NSAIDs, Colchicine Colchicine, CS (7.5 mg/d) CS (7.5 mg/d) 14.1±7.9 (12.5)
Anakinra re-Rx Total follow-up (months) Time to first recurrence after anakinra D/C (days) Initial treatment duration (months) Time to corticosteroid discontinuation (days) Baseline CRP (mg/dL)/time to normalisation (days) Disease duration Sex (months)
Details on patient demographics, treatment, and patient course during anakinra therapy Table 1
Recurrent idiopathic pericarditis is a common, problematic complication of acute pericarditis, occurring in approximately 30% of cases.1 Despite appropriate management with non-steroidal anti-inflammatory drugs (NSAIDs), colchicine and corticosteroids (CS), a number of patients are either resistant to treatment requiring long-term therapy with high doses of CS or intolerant to therapy.2–4 This disease is currently viewed as an autoinflammatory disease based on its clinical and laboratory features (recurrent episodes of sterile serosal inflammation in the absence of specific autoreactive antibodies or T cells),5–7 and the preliminary results showing favourable response to intereleukin-1 (IL-1) inhibition.8–10 Anakinra, a known IL-1 receptor antagonist, has been successfully used in small series of paediatric patients8 9 while we have recently first reported its efficacy and safety in three adult patients.10 In this report, we extend our follow-up on these three patients, and present data on seven more adult patients treated with anakinra. Ten patients with idiopathic, treatment-resistant recurrent pericarditis treated with anakinra were included in the study. The diagnosis of recurrent pericarditis was established by the following three criteria: (1) a documented initial episode of acute pericarditis, (2) reappearance of chest pain attributable to acute pericarditis and (3) at least one of the following findings: pericardial friction rub, fever, typical electrocardiographic changes, pericardial effusion (new appearing or worsening), and C reactive protein (CRP) elevation.1–3 In all patients, a specific cause of pericarditis was excluded after a thorough evaluation including detailed clinical history and examination, laboratory evaluation and imaging studies. All patients signed an informed consent form prior to enrolment, and the study was approved by the institutional review board. All patients were resistant and/ or intolerant to previous treatment with aspirin (ASA) and/or NSAIDs, colchicine and CS, while two (20%) had failed also azathioprine therapy (table 1). The mean number of previous recurrences was 8, the mean baseline dose of prednisolone was 14.1 mg/day (n=8, 2 patients had discontinued CS due to intolerance or side effects) and the mean baseline CRP level was 74 mg/dL. The treatment protocol of the initial three patients has been previously reported.10 The next seven patients (table 1, numbers 4–10), were given daily subcutaneous anakinra (100 mg) for 6 months followed by alternate day dosing for another 6 months. This modified protocol with slower tapering of anakinra was based on our initial10 and others’8 previous experience. CS and colchicine were gradually discontinued in all patients after initial anakinra administration. In patients who had a first recurrence after anakinra discontinuation, colchicine was reintroduced during the last month of anakinra therapy. Anakinra was highly effective in all cases leading to rapid symptom relief (within 48 h), CRP normalisation (mean time 5.9 days) and tapering/discontinuation of CS (median time to discontinuation 37.5 days) Five out of 7 patients (70%), relapsed shortly (mean time to relapse 18 days) after initial anakinra discontinuation. In 4/5 patients anakinra was restarted with immediate control of symptoms, while one patient was managed successfully with colchicine and NSAIDs alone.10 Anakinra administration was generally safe, except for minor
Total number of recurrences after anakinra D/C
Anakinra for the management of resistant idiopathic recurrent pericarditis. Initial experience in 10 adult cases
3 0 1 1 1 0 1 NA NA NA
ARD Online First, published on August 27, 2014 as 10.1136/annrheumdis-2014-205990 Letter
Ann2014. Rheum Produced Dis Month 2014 by Vol 0BMJ No 0 Publishing Group Ltd (& EULAR) under licence. 1 Copyright Article author (or their employer)
Downloaded from ard.bmj.com on August 31, 2014 - Published by group.bmj.com
Letter local reactions at the injection site (6/10, 60%) and transient transaminasemia requiring drug discontinuation in one patient (table 1, number 2). In conclusion, this study confirms our previous findings that anakinra is a rapidly acting, highly efficacious, safe and steroidsparing agent for the treatment of resistant recurrent idiopathic pericarditis in adults. Nevertheless, we observed a high recurrence rate (70%) which is even higher compared with the paediatric experience (43%)8 after anakinra discontinuation. Although these recurrences were easily managed with anakinra readministration, randomised controlled trials are required to confirm its efficacy and identify the most appropriate administration protocol.
Funding Special Account for Research Grants (SARG), National and Kapodistrian University of Athens, Athens, Greece.
George Lazaros,1 Panagiotis Vasileiou,1 Christos Koutsianas,2 Katerina Antonatou,2 Christodoulos Stefanadis,1 Dimitrios Pectasides,2 Dimitrios Vassilopoulos2
REFERENCES
1
1st Department of Cardiology, University of Athens Medical School, Hippokration General Hospital, Athens, Greece 2 2nd Department of Medicine and Laboratory, Clinical Immunology and Rheumatology Unit, University of Athens Medical School, Hippokration General Hospital, Athens, Greece Correspondence to Dr Dimitrios Vassilopoulos, Clinical Immunology and Rheumatology Unit, 2nd Department of Medicine and Laboratory, Hippokration General Hospital, University of Athens School of Medicine, 114 Vass. Sophias Ave., Athens 115 27, Greece; [email protected] Acknowledgements This work was supported, in part, by research grants from the Special Account for Research Grants (SARG), National and Kapodistrian University of Athens, Athens, Greece. Contributors GL: participated in study design and supervision; data acquisition, analysis and interpretation; and drafting, revision and final approval of the report; PV: participated in data acquisition, analysis and interpretation; drafting, revision and final approval of the manuscript; CK and KA: participated in data acquisition; drafting, revision and final approval of the manuscript; CS and DP: participated in study supervision; data interpretation; and drafting, revision and final approval of the report; DV: participated in study conception, design and supervision; data acquisition, analysis and interpretation; and drafting, revision and final approval of the report.
2
Competing interests None. Ethics approval Institutional Review Board, Hippokration General Hospital. Provenance and peer review Not commissioned; externally peer reviewed. To cite Lazaros G, Vasileiou P, Koutsianas C, et al. Ann Rheum Dis Published Online First: [ please include Day Month Year] doi:10.1136/annrheumdis-2014205990 Received 26 May 2014 Revised 6 August 2014 Accepted 10 August 2014 Ann Rheum Dis 2014;0:1–2. doi:10.1136/annrheumdis-2014-205990
1 2 3
4 5 6 7 8
9
10
Imazio M. Treatment of recurrent pericarditis. Expert Rev Cardiovasc Ther 2012;10:1165–72. Lazaros G, Vlachopoulos C, Stefanadis C. Idiopathic recurrent pericarditis: searching for Ariadne’s thread. Hellenic J Cardiol 2009;50:345–51. Imazio M, Belli R, Brucato A, et al. Efficacy and safety of colchicine for treatment of multiple recurrences of pericarditis (CORP-2): a multicentre, double-blind, placebo-controlled, randomised trial. Lancet 2014;383:2232–7. Brucato A, Brambilla G, Moreo A, et al. Long-term outcomes in difficult-to-treat patients with recurrent pericarditis. Am J Cardiol 2006;98:267–71. Maestroni S, Di Corato PR, Cumetti D, et al. Recurrent pericarditis: autoimmune or autoinflammatory? Autoimmun Rev 2012;12:60–5. Dinarello CA, van der Meer JW. Treating inflammation by blocking interleukin-1 in humans. Semin Immunol 2013;25:469–84. Vasileiou P, Tsioufis C, Lazaros G, et al. Interleukin-8 as a predictor of acute idiopathic pericarditis recurrences. A pilot study. Int J Cardiol 2014;172:e463–4. Finetti M, Insalaco A, Cantarini L, et al. Long-term efficacy of interleukin-1 receptor antagonist (anakinra) in corticosteroid-dependent and colchicine-resistant recurrent pericarditis. J Pediatr 2014;164:1425–31.e1. Picco P, Brisca G, Traverso F, et al. Successful treatment of idiopathic recurrent pericarditis in children with interleukin-1beta receptor antagonist (anakinra): an unrecognized autoinflammatory disease? Arthritis Rheum 2009;60:264–8. Vassilopoulos D, Lazaros G, Tsioufis C, et al. Successful treatment of adult patients with idiopathic recurrent pericarditis with an interleukin-1 receptor antagonist (anakinra). Int J Cardiol 2012;160:66–8.
Ann Rheum Dis Month 2014 Vol 0 No 0
Downloaded from ard.bmj.com on August 31, 2014 - Published by group.bmj.com
Anakinra for the management of resistant idiopathic recurrent pericarditis. Initial experience in 10 adult cases George Lazaros, Panagiotis Vasileiou, Christos Koutsianas, et al. Ann Rheum Dis published online August 27, 2014
doi: 10.1136/annrheumdis-2014-205990
Updated information and services can be found at: http://ard.bmj.com/content/early/2014/08/27/annrheumdis-2014-205990.full.html
These include:
References
This article cites 10 articles http://ard.bmj.com/content/early/2014/08/27/annrheumdis-2014-205990.full.html#ref-list-1
P
